Role of Histamine in Liver Ischemia-Reperfusion Injury-Implication for H1 Receptor Antagonist in the Clinical Application.

Abstract

BACKGROUND: Liver ischemia-reperfusion injury (IRI) is a critical complication of liver resection and transplantation. Our previous research demonstrated that preoperative fasting regimen significantly mitigated liver IRI in mice, whereas how fasting alleviates liver IRI remains largely unknown. In this study, we aimed to identify the metabolites that contribute to the pathology of liver IRI and to investigate their roles in modulating liver damage. METHODS: Comprehensive metabolomic analysis was performed on liver tissues obtained from wild-type (WT) mice subjected to partial warm liver ischemia and reperfusion with and without preoperative fasting. To investigate the role of histamine in liver IRI, histamine H1 receptor knockout (Hrh1KO) and WT mice were exposed to liver IRI. Some WT and Hrh1KO mice were pretreated with H1-antihistamines before the ischemia challenge. RESULTS: Among the identified metabolites, histamine displayed a distinctive pattern, with significantly elevated levels in the ischemia and reperfusion insult group without preoperative fasting and substantially reduced levels in the preoperative fasting group. Significant amelioration of liver IRI was observed in Hrh1KO mice, accompanied by a profound reduction in the release of high-mobility group box 1 into the bloodstream. Furthermore, administration of H1-antihistamines, which block histamine binding to the histamine H1 receptor (H1R) and suppress basal H1R activity, significantly inhibited high-mobility group box 1 release and ameliorated liver IRI. CONCLUSIONS: Histamine is a key metabolite that exacerbates liver IRI via H1R-mediated signaling pathways. These findings highlight the potential of H1-antihistamines as a promising therapeutic approach for mitigating liver injury associated with liver surgery and liver transplantation.